[The use of hyperimmune anti-cytomegalovirus immunoglobulins in HIV infection]. / Impiego delle immunoglobuline iperimmuni anti-cytomegalovirus in corso di infezione da HIV.

Cytomegalovirus (CMV) is one of the most frequent opportunistic agents that affects HIV positive subjects. The prophylaxis and treatment of cytomegalovirus infection in HIV positive subjects represent difficult and controversial problems. In this study we evaluated efficacy of anti-CMV immunoglobulins (derived from plasma with a high titer of CMV anti-bodies) in primary and in secondary prophylaxis for CMV disease in adults with severe immunodeficiency caused by HIV infection. For primary prophylaxis, in 22 patients with CD4 < 200/mmc enrolled to receive a monthly infusion of intravenous immunoglobulins (IVIG) at 200 mg/kg we observed prophylactic effect for the prevention of CMV and bacterial infections. Concerning secondary prophylaxis, 7 patients with CMV manifestation treated after remission with anti-CMV IVIG at 200 mg/kg every two weeks, had a low frequency of relapse and a good clinical outcome. Because their tolerability, anti-CMV immunoglobulins are an interesting option particularly for the prevention of CMV and bacterial infection in HIV-positive adults in advanced stages of disease.

Comparative activity of idarubicin and idarubicinol in combination with cyclosporin A in multidrug-resistant leukemia cells.

4-Demethoxydaunorubicin (idarubicin, IDA) is an anthracycline that has shown good cytotoxic activity in vitro against tumor cell lines displaying the multidrug-resistant (MDR) phenotype. IDA is converted in the liver into idarubicinol (2HIDA) and, in this form, seems to exert its antitumoral activity in vivo. Recent studies have shown that 2HIDA has tumoricidal activity similar to that of the parent drug when tested in vitro in sensitive neoplastic cells. In this work we compared in vitro the effects of IDA and 2HIDA used alone and in combination with 2 microM cyclosporin A (CyA) in the MDR leukemic cell lines FLCR and K562R and in their sensitive parent cell lines FLC and K562. IDA and 2HIDA showed the same cytotoxic activity in sensitive cells. After 1 h of exposure of cells to each anthracycline, we observed that the cellular uptake of IDA and 2HIDA was also similar. In resistant cells, 2HIDA was 3-4 times less active than IDA. We observed that the intracellular uptake of 2HIDA was lower than that of IDA, and this may be correlated with a greater ability of P-glycoprotein to expel 2HIDA as opposed to IDA. Indeed, when MDR cells were exposed to IDA and 2HIDA in combination with 2 microM CyA, the cytotoxic effect of these anthracyclines was the same, and it was similar to that observed in sensitive cells. These data confirm the utility of the combination of IDA and an MDR-reversing agent in hematological malignancies displaying the MDR phenotype.

Phase III comparative trial using CHOP vs CIOP in the treatment of advanced intermediate-grade non-Hodgkin's lymphoma.

Until now, literature data support the fact that the CHOP regimen represents the standard first line treatment for patients with advanced intermediate-grade non-Hodgkin's lymphoma. Recently, idarubicin has been introduced in clinical trials because of its favourable preclinical profile: it is more active than daunorubicin and doxorubicin against a number of experimental tumour systems and is significantly less cardiotoxic in animal models. From March 1991 to June 1993, 115 previously untreated patients with stage II to IV intermediate-grade non-Hodgkin's lymphoma, according to the Kiel classification, were enrolled in a phase III comparative trial. The objectives of the study were to compare the efficacy and safety of using idarubicin instead of doxorubicin in the polychemotherapeutic regimen CHOP (cyclophosphamide, doxorubicin, vincristine, and dexamethasone). Of the 115 patients registered for the trial, 103 were evaluable: 52 received CH (doxorubicin)OP and 51 received CI(Idarubicin)OP. Known prognostic factors were equally distributed among the two groups. There were no significant differences between the 2 groups in the rates of partial and complete response. The overall response rate was 87%, with complete response in 62%: 63% in the CHOP group, and 59% in the CIOP group. At 30 months (median 20 months), 86% of all CR patients were alive without disease in the CHOP group and 85% in the CIOP group. Patients treated with CHOP experienced severe alopecia more frequently (P = .004). Only three patients in the CIOP group showed cardiac adverse events (1 moderate and 2 mild), while in the CHOP group 4 mild, 2 moderate and 1 severe were recorded. LVEF monitoring was carried out in 31 patients of the CHOP group and in 27 of the CIOP group. A median drop of 8.3% of the LVEF was observed in patients treated with CHOP regimen as compared to 4.8% in patients with CIOP regimen (P = .0001). In this trial, the "idarubicin arm" (CIOP regimen) was found to have an equivalent therapeutic efficacy and, slightly, reduced clinical toxicity in comparison to the standard doxorubicin-containing CHOP regimen in patients with intermediate-grade non-Hodgkin's lymphoma.

Effects of R-enantiomer (GR66234A) and L-enantiomer (GR66235A) of telupidine, a new dihydropyridine derivative, on cell lines displaying the multidrug resistant phenotype.

BACKGROUND: Many dihydropyridine analogues with calcium channel blocker activity are able to reverse multidrug resistance (MDR). We studied the daunorubicin resistance reversing activity of the R enantiomer (GR66234A) and the L-enantiomer (GR66235 A) of teludipine, a new lipophilic calcium channel blocker synthesized by Glaxo. METHODS: The daunorubicin resistance reversing activity of the enantiomers of teludipine was evaluated in two MDR cell lines: ARNII, an erythroleukemia cell line which expresses p-glycoprotein, and MCF 7/R, a breast cancer cell line with p-glycoprotein and high levels of glutathione S transferase (GST) and glutathione peroxidase (GSH Px). RESULTS: GR66234A and GR66235A show the same activity in reversing daunorubicin resistance and are more effective than verapamil. The difference in activity between verapamil and the enantiomers of teludipine is greater in ARNII cells than in MCF 7/R cells. Nevertheless, there are no significative differences in cellular daunorubicin accumulation between ARNII and MCF 7/R following exposure to teludipine, nor are there differences in intracellular daunorubicin distribution in the presence of either MDR reversing agent. CONCLUSIONS: The low calcium channel antagonistic activity of GR66234A suggests that this compound may be useful in combination with chemotherapy in MDR malignancies.

Anthracycline containing regimens in intermediate grade lymphoma. Italian Cooperative Study Group on Intermediate Grade Malignant Lymphoma.

From March 1991 to April 1992, 44 previously untreated patients with stage II to IV intermediate-grade non-Hodgkin's lymphoma (according to the Kiel classification) were entered in a phase III comparative trial. The objectives of the study were to compare the efficacy and safety of using idarubicin instead of doxorubicin in the combination chemotherapeutic regimen CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone). Forty-four patients were randomly assigned to receive either CI(idarubicin)OP or CH(doxorubicin)OP. The study is ongoing and so far no significant differences in complete response rate and (non-)hematologic toxicity have been observed.

Selection of a new multidrug resistant cell line from Friend leukemia cells by short and cyclic exposures to high concentrations of daunorubicin.

BACKGROUND: Resistance of tumor cells to cytotoxic agents can be due to the overexpression of the mdr 1 gene, which encodes a plasma membrane protein (P-glycoprotein). To understand the molecular basis of multidrug resistance, several laboratories have isolated cell lines resistant to doxorubicin, actinomycin D, vinca alkaloids and related agents. Many months or years of culture with gradually increasing concentrations of cytotoxic agents are necessary to obtain a resistant cell line. METHODS: We selected a new multidrug resistant cell line (MELC-DRTL) by 24-hour cycles of exposure to relatively high concentrations of daunorubicin from sensitive Friend Leukemia cells. After each cycle, the residual live cells were expanded up to the density of 1 x 10(6) cells/ml. RESULTS: The assay conducted with MoAb C-219 showed a high expression on the membrane surface of P-glycoprotein in the MELC-DRTL line, but the fact that it was impossible to obtain a complete reversal of the resistance, even when using high concentrations of verapamil, suggests the presence of other mechanisms unrelated to the presence of P-glycoprotein. CONCLUSIONS: The kind of cellular resistance induction used in this experiment enabled us to obtain an MDR cell line in three months of culture.

Alpha-interferon in polycythemia vera and essential thrombocythemia.

Twenty-one patients with chronic myeloproliferative disorders, eleven with polycythemia vera (PV) and ten with essential thrombocythemia (ET), were treated with small doses of alpha-2a interferon (IFN). The median follow-up was, respectively, 10.8 months (range 4-22) for PV and 8.11 months (range 4-16) for ET. Six patients with PV and five with ET had been previously treated with conventional cytotoxic drugs, while the remaining patients were newly diagnosed. In four patients with PV we observed a durable normal hematocrit level (PCV less than 0.48) and a reduction of platelet count and spleen size within 4-8 weeks of treatment. Three patients achieved moderate disease control. In the others the disease remained substantially unchanged. Five out of nine evaluable patients with ET showed complete response (CR) within six weeks, one patient had a partial response (PR) and three no response (NR). In one patient with ET the IFN therapy was stopped after twelve days because neurological side effects were observed. All the other patients tolerated long-term treatment very well.

Hodgkin's Disease in 50 Intravenous Drug Users with HIV-Infection.

Fifty cases of Hodgkin's disease in intravenous drug users (IVDU) have been collected by the Italian Cooperative Group on AIDS-Related Tumors (G.I.C.A.T.). Ninety-two per cent of the patients were males; the median age was 26 years. Persistent generalized lymphadenopathy (PGL) at onset was present in 54% of patients, AIDS in 9%, ARC in 9% while 28% were simply HIV-positive. The initial median absolute number of CD4 lymphocytes was 264/mmc. Opportunistic infections were diagnosed in 20% of patients. In most patients the histological pattern was that of mixed cellularity and lymphocytic depletion (76%). In almost half the initial symptom was a persistent lymph node enlargement due to PGL. In the majority of patients (58%) only a clinical staging and bone marrow biopsy could be performed due to the presence of opportunistic infections, rapid disease progression or refusal of pathologic staging procedures. One patient presented with a Waldeyer's ring involvement, but no other unusual presentations were observed. After MOPP alternated or followed by ABVD or MOPP alone, 15/29 CR (52%) and 14/29 PR (48%) were observed. The median duration of CR was 14 months, while the median survival of CR has not been reached; the median survival of patients treated with chemotherapy with CD4 values at presentation {geq}400/mmc was significantly superior to that in those with CD4 < 400/mmc. The overall median survival was 16 months. Twenty-eight per cent of patients receiving chemotherapy + radiotherapy developed opportunistic as well as non-opportunistic infections (21%). Lethal hepatic toxicity was observed in 2 patients. In conclusion, Hodgkin's disease in IVDU was not found to be associated with unusual presentations, as previously reported for homosexuals. Complete remissions could be achieved in over 50% of patients, but in IVDU non-opportunistic infections in addition to opportunistic infections may also limit treatment administration. The presence of parenchymal functional impairment due to drug abuse, or drug abuse-related infections, such as pneumonia, endocarditis and hepatitis, should lead to the choice of antitumour agents with no or only minor potential liver, lung and cardiac toxicity.

[Minimal residual disease in hematological neoplasms]. / La malattia minima residua nelle neoplasie ematologiche.

The existence of neoplastic cells with low or no sensibility to antiblastic drugs represents the most important cause of relapse in hematological malignancies. The amount of leukemic cells that remains after antiblastic chemotherapy represents the minimal residual disease. These cells can re-expand at any moment, even after months or years, causing short-term or long-term relapse. The minimal residual disease is not always detectable with morphological examination. The recent utilization of techniques such as cell culture by stimulation with growth factors and genetic amplification have made it possible to reach resolutions of more than 1-10(5) cells. The therapeutic strategies for total eradication of residual neoplastic cells are currently under investigation. The combined use of biological responder modifiers with chemotherapy or the use of immunotherapy with Interleukin-2 or LAK cells has provided one possible solution to this problem.

[Potentiation of the antiblastic activity of mafosfamide by GM-CSF and interleukin-3: a possible use in the treatment of acute myeloblastic leukemia]. / Potenziamento dell'attività antiblastica della mafosfamide mediante GM-CSF e interleuchina-3: una possibile applicazione nel trattamento delle leucemie acute mieloblastiche.

The low activity of antiblastic drugs on tumor cells in the G0 phase is an important limitation in the therapy of malignancies. Cells in the G0 phase are able to enter in cycle any time after chemotherapy treatment, causing relapse of the disease. The use of colony stimulating factors (for example granulocyte-macrophage stimulating factor-GM-CSF and interleukin 3-IL-3) permits the recruitment in cycle of myeloblastic leukemic cells in the G0 phase and thus a cellular population sensitive to chemotherapy. We evaluated the in vitro activity of GM-CSF and IL-3 in fresh myeloblastic leukemic cells: after 96 h of incubation with GM-CSF (500 U/mL), IL-3 (500 U/mL), and GM-CSF + IL-3 (500 + 500 U/mL), 10(6) cells were treated with mafosfamide (30 microgram/mL x 30 min); 10(6) cells were simultaneously treated with mafosfamide without preincubation with colony stimulating factors. The sensitivity of leukemic cells preincubated with GM-CSF and IL-3 to the cytotoxic action of mafosfamide was greater than that of the control cells treated with mafosfamide alone. No enhancement of cytotoxic activity of mafosfamide was observed with GM-CSF + IL-3 combined treatment. The use of colony stimulating factors may effectively increase the number of leukemic cells sensitive to alkylating drugs.

[Use of immunoglobulins in AIDS]. / Uso delle immunoglobuline in corso di AIDS.

Fourteen AIDS patients with constitutional symptoms without a known etiology were treated with intravenous immunoglobulins (IVIG). The dosage regimen was 300 mg/kg per day three times weekly for two weeks followed by 300 mg/kg per day once weekly for ten weeks. All patients improved clinically after treatment with IVIG. The reason for the clinical improvement in our cases is as yet unclear, but it is possible that immunoglobulins have had a therapeutic effect on the underlying immunologic disturbance.

Pefloxacin in the antibacterial treatment of immunodepressed patients.

Pefloxacin 800 to 1200 mg daily was given for 3 to 20 days, orally or intravenously, to 84 immunocompromised patients. Five patients dropped out because of side effects and 2 for other causes. Treatment efficacy was evaluated in 77 patients, 43 men and 34 women, aged 18 to 80 years. Immunodepression resulted from malignancy in 46 patients, LAS/ARC or AIDS in 28, and from unknown causes in 3. Fifty-eight patients had documented infections (respiratory-tract infections 29, urinary-tract infections 13, septicemia 10, other 6) and 19 had a fever of unknown origin (FUO). Cure or significant improvement of symptoms was achieved in 81% of patients with documented infections and in 74% of patients with FUO. Side effects (mainly gastrointestinal disturbances and skin rash) occurred in 7 patients (8.2%), including dropouts. These results suggest that pefloxacin may be useful for the antibacterial treatment of immunodepressed patients.

Chronic lymphocytic leukemia (CLL) in younger adults: a retrospective study of 133 cases.

Clinical and biological data have been evaluated, using both univariate and Cox's multivariate statistical analyses, in a series of 133 Chronic Lymphocytic Leukemia (CLL) patients with a mean age of 46.6 years (range 31-50). In univariate analyses, anemia (Hb less than 13 g/dl), peripheral blood (PB) lymphocytosis (greater than 40 x 10(9)/l) and bone marrow (BM) lymphocytosis (greater than 80 per cent) were shown to be of significant prognostic value. Multivariate analysis, through a forward stepwise procedure, showed that the most important and independent variable is the BM lymphocytosis. These results are different from those obtained in previous studies and particularly in a recent identical study performed by the same Cooperative Group on 1777 patients with a mean age of 64.2 years (Mandelli et al., 1987). No significance can be demonstrated in stratifying this series of younger patients according to different staging methods (Rai et al., 1975; Binet et al., 1981b; Mandelli et al., 1987). Therefore this population of CLL patients, with less than 50 years of age, has risk factors quite different from classical CLL. The results of the present study show that the diagnostic approach to B-CLL in younger adults must be more complete: using the common diagnostic criteria, established staging systems appear to be inadequate in this series of younger patients.

Double-stranded RNA excess in hematologic diseases: clinical implications.

Evaluation of double-stranded RNA by flow cytometric analysis is an important parameter for discriminating quantitatively between human tumoral and normal cells. We studied double-stranded RNA (ds-RNA) measurements using propidium-iodide after DNase treatment in bone marrow and in peripheral blood cells from patients with acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia and multiple myeloma. The highest incidence of ds-RNA excess (greater than 30%) was observed in patients with acute leukemia (75%), while those displaying it in complete remission phase were 20-25% and in relapse about 80%. A high incidence was also noted in patients with chronic myeloid leukemia in blastic crisis (100%) and in patients with multiple myeloma with heavy tumor stage myeloma (78%). We never observed an elevated ds-RNA excess in the control group, formed by normal peripheral blood lymphocytes. Indeed the specificity of this tumor marker is attested to not only by its high levels in various hematologic malignancies, but also by its absence in normal cells. Hence the importance of its clinical implications in malignant hematologic diseases is confirmed.

Hodgkin's disease in association with acquired immunodeficiency syndrome (AIDS). A report on 36 patients. Gruppo Italiano Cooperativo AIDS and Tumori.

In an Italian cooperative study on AIDS and cancer a diagnosis of Hodgkin's disease was established in 36 HIV-positive patients. The series was characterized by a high proportion of drug abusers, a high proportion of mixed cellularity and lymphocytic depletion subtypes and short survival. It is still unclear if HIV infection promotes the development of Hodgkin's disease or only modifies the course of the disease. According to the authors, however, patients who are HIV seropositive and have biopsy-proven Hodgkin's disease should be considered as fulfilling the criteria for AIDS.

Prognosis in chronic lymphocytic leukemia: a retrospective multicentric study from the GIMEMA group.

Clinical and biological data were evaluated using Desu univariate analyses or Cox multivariate analyses in a series of 1,777 chronic lymphocytic leukemia (CLL) patients from an Italian Cooperative Group. In univariate analyses, age and sex of patients, presence of bone marrow (BM; greater than or equal to 50%), and peripheral blood (PB; greater than or equal to 60,000/microL) lymphocytosis, anemia (hemoglobin [Hb] less than 11 g/dL), thrombocytopenia (less than 100,000/microL), direct Coombs' test positivity, hepatomegaly, splenomegaly, and extent of lymph node involvement were shown to be of significant prognostic value. Multivariate analyses, through a stepwise procedure, showed that the most important prognostic variables are Hb, hepatomegaly, lymph node involvement, PB lymphocytosis, and age and sex of patients. Further covariates would produce an improvement having a nonsignificant P value. Based on the results of multivariate analyses, a four-step staging using the significant variables of the Cox model is proposed.